Seasonal affective disorder (SAD) is characterized by recurrent depressive episodes with a seasonal pattern, most often occurring in fall and winter. Although the mechanisms underlying SAD remain unknown, one hypothesis postulates abnormalities in response to seasonal variation in day light. This is suggested by the regular winter timing of depressive episodes, seasonal changes in biology, and the benefit of light therapy (LT) for SAD. A decreased response to light among SAD patients may be the result of abnormal retinal signaling, such that low day light levels in the winter fall below a required threshold, leading to depression. Abnormal retinal responses could be due to abnormalities in a recently discovered class of retinal ganglion cells that express the protein melanopsin and convey information to the circadian clock about day length. These cells also drive a portion of the pupil light reflex termed the post-illumination pupil response (PIPR), in which the pupil constricts after light offset. Studies have found that mice missing the melanopsin gene have a reduced PIPR compared to that seen in normal mice. A melanopsin pathway with reduced sensitivity could explain the risk for SAD. In support of this hypothesis, we recently found that SAD patients have a higher frequency of a particular sequence variation in the melanopsin gene. We will now test if those with SAD have a diminished PIPR compared to healthy controls, as well as the following other hypotheses. The specific objectives of this proposal are three-fold: (1) To determine if individuals with SAD differ in the PIPR relative to nonseasonal, nondepressed controls and in comparison to individuals with a history of nonseasonal Major Depressive Disorder. We will use a specific wavelength of blue light to which melanopsin is most sensitive. Based on animal studies and our preliminary data, we predict that individuals with SAD will have a diminished PIPR to blue light relative to individuals who do not have a history of depression, and relative to individuals with a nonseasonal depression pattern. (2) To determine if individuals with SAD vary across the seasons on the PIPR in comparison to controls. (3) To determine if individuals with coding variations in the gene for melanopsin differ on the PIPR. These tests will allow us to determine if the melanopsin-driven PIPR differs on the basis of depression diagnosis, seasonal pattern of depressive episodes, season of measurement, or sequence variations in the melanopsin gene. Our preliminary data indicate that individuals with SAD have a diminished PIPR to blue light. If the abnormal response to seasonal reductions in day light in SAD stems from low melanopsin cell sensitivity, it is possible that the PIPR may serve as a biomarker for SAD. Secondly, to the extent that abnormal responses to light may be mediated by melanopsin, genetic variation in the melanopsin pathway might be expected to predict PIPR deficits. If confirmed, these observations would contribute to our understanding of the mechanisms underlying a seasonal pattern of depression and possibly identify a clinically useful marker of risk for SAD. PUBLIC HEALTH RELEVANCE: Major depression is a highly prevalent, chronic, and debilitating mental health problem with significant social cost that poses a tremendous economic burden. Winter seasonal affective disorder (SAD) is a subtype of recurrent major depression involving substantial depressive symptoms that adversely affect the family and workplace for about 5 months of each year during most years, beginning in young adulthood. This proposal aims to study the role of the melanopsin pathway in SAD, in the hopes of better understanding the biological etiology of SAD. There are several treatments available for SAD, and not all individuals respond to the first-line treatment of light therapy. Therefore, better understanding o the biology behind this disorder could lead to better treatment protocols that might reduce the likelihood of treatment failure and shorten time to remission by potentially avoiding ineffective treatment.